Obesity is strongly linked to the development of osteoarthritis (OA); however, the mechanisms involved are not clearly understood. Accumulation of lipids/free fatty acids (FFA) in non-adipose tissue results in lipid toxicity, characterized by cell dysfunction, inflammation, and cell death. One of the mechanisms proposed for lipid toxicity is induction of endoplasmic reticulum (ER) stress. Our preliminary studies showed that mice fed a high- fat diet developed more severe OA than mice fed a low-fat diet. Immunohistochemical studies of the joint tissue from these mice showed increased expression of CHOP, a molecular marker of ER stress, compared to mice on a low-fat diet. In addition, our in vitro data suggest that lipid toxicity activates the ER stress transducer IRE1? in chondrocytes, and elicits inflammatory and pro-apoptotic pathways. Thus, we have both in vivo and in vitro evidence suggesting that ER stress is mechanistic link between high-fat diet and OA. The overall goals of this project are to determine (a) if lipid toxicity promotes joint tissue destruction and development of OA by inducing ER stress and the unfolded protein response (UPR), and (b) elucidate the mechanism(s) involved. Hence we propose 3 Specific Aims: Aim 1.To determine OA severity in CHOP-deficient mice fed a high-fat diet. Aim 2: To determine OA severity in IRE1?-deficient mice fed a high-fat diet. Aim 3: To determine if dietary supplementation of palmitate (palm oil) promotes ER stress and OA in mice. The successful completion of our project will establish ER stress as a mechanistic link between a high-fat diet, and OA, and provide new targets for improved therapeutic treatments for OA or - ideally - interventions to halt its progression.